1. Field of Invention
The present invention relates to novel compounds and compositions, useful for the treatment of certain metabolic diseases.
2. Prior Art
The pharmacologic and therapeutic properties of salts of dichloroacetec acid (DCA) have been extensively studied over the last several years. Researchers have found that DCA stimulates glucose uptake and utilization by peripheral tissues [Stacpoole et al., Metabolism, 19:71 (1970); McAllister et al., Biochem. J. 134:1067 (1973); Diamond et al., Diabetes 31:326 (1982)] and inhibits hepatic glucose production [Stacpoole, Metabolism26:107 (1977); Demangre et al., Biochem. J. 172:91 (1978); Diamond et al., Metabolism 30:880 (1981)]. It has also been found to decrease blood glucose levels in patients with diabetes mellitus [Stacpoole et al., N. Eng. J. Med. 298:526 (1978)]. DCA also stimulates lactic acid oxidation in animal tissues and significantly decreases lactic acid levels and overall morbidity in patients with lactic acidosis [Stacpoole et al., N. Eng. J. Med 309:390 (1983); Blackshear et al., Diabetes Care 5:391 (1982)]. In addition, DCA reduces circulating triglyceride and cholesterol concentrations in obese [Felts et al., Diabetes, 25 (suppl):363 (1976)] and diabetic [Hayek et al., Metabolism 29:120 (1980); Riles et al., Diabetes 28:852 (1979) animals. DCA also markedly decreases blood cholesterol levels in patients with various forms of hyperlipidemia [Stacpoole et al., N. Eng. J. Med. 298:526 (1978); Moore et al., Atherosclerosis 33:285 (1979)].
The efficacy of DCA for the treatment of metabolic disorders, however, is compromised by the fact that DCA is toxic to lower animals and humans, particularly upon chromic administration. It has been reported that a human patient who received DCA for about four months developed a mild polyneuropathy that resolved when treatment stopped [Moore et al., ibid.]. Chronic administration of DCA to lower animals in doses exceeding those used clinically also induces a reversible peripheral neuropathy, changes in testicular morphology and lenticular opacities [Stacpoole, N. Eng. J. Med. 300:372 (1979)].
DCA is known to oxidize in vivo to glyoxylate and subsequently to oxalate [Demangre et al., Biochem. Biophys. Res. Comm. 85:1180 (1978); Harris et al., Arch. Biochem. Biophys. 189:364 (1978)]. Oxalate is known to cause neurotoxicy [Bilbao et al., Can. J. Neurol. Sci. 3:63 (1976)] and lenticular opacities [Fielder et al., Br. J. Ophthal. 64:782 (1980)], and may be at least partly responsible for the toxic effects associated with the chronic administration of DCA.
It is an object of the present invention to ameliorate the toxicity associated with DCA and provide compounds, compositions and methods for safe and effective treatment of certain metabolic disorders.